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TMC278 Matches Efavirenz in Treatment-Naive People
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Mark Mascolini
February 28, 2007
14th Conference on Retroviruses and Opportunistic Infections
Los Angeles
TMC278, a nonnucleoside being tested in people with resistant virus [1], matched efavirenz virologically in previously untreated people taking the drug for 48 weeks [2]. Results of the randomized trial outlined at the 14th Conference on Retroviruses suggested TMC278 may cause fewer central nervous system side effects and less rash than efavirenz.
Anton Pozniak (Chelsea and Westminster Hospital, London) and worldwide coworkers randomized 368 antiretroviral-naive people to efavirenz or to one of three TMC278 doses--25, 75, or 150 mg once daily. While three quarters of enrollees added Combivir (AZT/3TC) to their nonnucleoside, one quarter added Truvada (tenofovir/emtricitabine). Pretreatment median viral loads stood at 69,000 copies in the combined TMC278 arms and 75,000 copies in the efavirenz group. Respective starting CD4 counts measured 200 and 207 cells. Study participants had been infected with HIV for about 1 year.
The primary endpoint, 48-week time to loss of virologic response at the 50-copy level, reflected equivalent responses in the four treatment arms--81% with efavirenz and 25 mg of TMC278, 80% with 75 mg of TMC278, and 79% with 150 mg of TMC278. On-treatment 48-week sub-50 responses measured about 90% in all four arms. Pozniak counted 8 virologic failures (9%) in the 25-mg group, 5 (5%) in the 75-mg group, 6 (7%) in the 150-mg group, and 5 (6%) in the efavirenz group.
A slightly higher proportion of people taking the highest dose of TMC278 (10%) dropped out because of side effects than dropped out of the other three arms for that reason (5% to 6%). Pozniak did not see more lipid abnormalities with higher doses of TMC278, but there may have been more rash with higher doses.
Nervous system problems like headache, dizziness, and sleepiness affected more people taking efavirenz (53%) than TMC278 (33%). Vertigo troubled 11% taking efavirenz and 1% taking TMC278. Rashes flared in 19% randomized to efavirenz and 8% randomized to TMC278, but all rashes were grade 1 or 2 except for a grade-3 rash in a person taking 75 mg of TMC278 with dapsone.
About 10% taking either efavirenz or TMC278 had a serious adverse event (SAE). But incidence of grade 3 or 4 SAEs reached 25% in the combined TMC278 arms versus 16% in the efavirenz arms. Pozniak blamed that difference on more investigator-reported SAEs in the TMC278 arm and possible underreporting in the efavirenz arm. Actual grade 3 or 4 lab abnormalities did not differ between the efavirenz group and the combined TMC278 arms.
Total cholesterol and "bad" high-density lipoprotein cholesterol rose more with efavirenz than TMC278, but people taking efavirenz also gained more "good" high-density lipoprotein (HDL) cholesterol. The total-to-HDL cholesterol ratio was similar in the two groups. People taking efavirenz gained an average 18 mg/dL of triglycerides, whereas triglycerides fell 10 mg/dL in the combined TMC278 groups.
Work so far discloses no teratogenicity with TMC278, a problem that prevents efavirenz treatment of pregnant women or women who may become pregnant. All women enrolled in this trial took contraceptives.
Tibotec will develop the 75-mg once-daily dose for treatment-naive people.
References
1. de Bethune MP, Andries K, Azijn H, et al. TMC278, a new potent NNRTI with an increased barrier to resistance and good pharmacokinetic profile. Twelfth Conference on Retroviruses and Opportunistic Infections. February 22, 25, 2005. Boston. Abstract 556.
2. Pozniak A, Morales-Ramirez J, Mohapi L, et al. 48-Week primary analysis of trial TMC278-C204: TMC278 demonstrates potent and sustained efficacy in ART-naive patients. 14th Conference on Retroviruses and Opportunistic Infections. February 25-28, 2007. Los Angeles. Abstract 144LB.
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